Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes

Abstract

Therapies targeted at fundamental processes of aging may hold great promise for enhancing the health of a wide population by delaying or preventing a range of age-related diseases and conditions-a concept dubbed the "geroscience hypothesis." Early, proof-of-concept clinical trials will be a key step in the translation of therapies emerging from model organism and preclinical studies into clinical practice. This article summarizes the outcomes of an international meeting partly funded through the NIH R24 Geroscience Network, whose purpose was to generate concepts and frameworks for early, proof-of-concept clinical trials for therapeutic interventions that target fundamental processes of aging. The goals of proof-of-concept trials include generating preliminary signals of efficacy in an aging-related disease or outcome that will reduce the risk of conducting larger trials, contributing data and biological samples to support larger-scale research by strategic networks, and furthering a dialogue with regulatory agencies on appropriate registration indications. We describe three frameworks for proof-of-concept trials that target age-related chronic diseases, geriatric syndromes, or resilience to stressors. We propose strategic infrastructure and shared resources that could accelerate development of therapies that target fundamental aging processes.

Keywords: Aging; Clinical trials; Geroscience Network.

Figure 1.

Pipeline of drug development for interventions that target fundamental aging processes. As in other fields, numerous potential interventions will be winnowed in the preclinical phase, with those showing the most promise for targeting the biology of aging progressing to initial safety studies in humans. Small proof-of-concept clinical trials might then “de-risk” these candidate interventions by providing signals of efficacy and further safety data to better predict success in large clinical trials designed to support Food and Drug Administration approval.

Figure 2.

Frameworks and goals for proof-of-concept clinical trials of interventions that target fundamental aging processes. These interventions are hypothesized to affect multiple age-related diseases and conditions: the “geroscience hypothesis.” Three frameworks are presented for the design of clinical trials to test these interventions for effects on outcomes related to age-related diseases, geriatric syndromes, and resiliency. Proof-of-concept clinical trials would test the geroscience hypothesis, but also provide evidence of efficacy in the outcome being targeted, as well as data and samples for further research. Ultimately, proof-of-concept trials will help justify and in the design of larger clinical trials and support new regulatory indications for interventions that target fundamental aging processes.

Figure 3.

Proposed development of shared resources and strategic infrastructure to accelerate progress through early clinical trials of interventions targeting fundamental aging processes. Many of these shared resources might be coordinated by new Geroscience Translational Network Centers, which would specialize in particular aspects of preclinical basic research, clinical trial support, and training.